Embodiments disclosed herein relate to compositions of norketotifen that are intended for the treatment of ocular disorders, such as xerophthalmic disorders, allergic disorders and inflammatory disorders as well as combinations thereof, and methods of treating ocular disorders by administration of such compositions. The term “xerophthalmia” as used herein refers to conditions that are also called xerophthalmic disorders, keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, dry eye syndrome, or dry eyes. The present invention also relates to formulations of norketotifen that are intended for the treatment of allergic (atopic) ocular diseases, such as for example allergic conjunctivitis and various other types of ocular inflammatory diseases, such as for example keratitis, keratoconjunctivitis, non-allergic conjunctivitis and various forms of blepharitis (inflammation of the eyelids).
Norketotifen is an active metabolite of ketotifen (Zaditor®, Novartis), which is used as an ocular medication for allergic disorders. Norketotifen has antihistaminic activity (Kennedy G R, 1982) that is about half of that of ketotifen when tested in vivo (Example 12.) Norketotifen is about ten times more active than ketotifen as anti-inflammatory compound Example 13.)

Ketotifen is available commercially, for example from Sigma-Aldrich (Internet: Sigma-Aldrich.com/order). Norketotifen can be made by demethylation of ketotifen according to the method described by Waldvogel et al. 1976, which publication is hereby incorporated by reference. However, this use of norketotifen is limited by its inherent irritability, as well as the irritability of certain excipients that were previously thought necessary to formulate an effective medicament, taking into account various issues including the limited solubility of the active ingredient norketotifen.
As described in U.S. Pat. No. 6,207,684, racemic norketotifen is useful for the treatment of various ocular conditions, such as for example conjunctivitis and keratitis. Further descriptions concerning S-norketotifen and R-norketotifen were presented in U.S. Pat. Nos. 7,226,934 and 7,557,128, respectively. Said patents are hereby incorporated by reference. It has now been found that selected formulations of norketotifen are well tolerated by mammalian ocular tissues and have the surprising effect of decreasing or eliminating the ocular irritating activity of norketotifen when applied to the eye. Said selected formulations (herein called “preferred formulations”) of norketotifen are suitable for daily topical administrations. Ocular administration of ophthalmic medication is the preferred route of administration.
Due to its physicochemical properties and its pharmacological effects, such as low anti-muscarinic activity, norketotifen is well suited for ocular use.
To our knowledge, methods of administering norketotifen in a preferred formulation topically to the eye or into the conjunctival sac of patients suffering from eye disorders have not previously been described. The therapeutic use of selected ocular formulations containing norketotifen has not been described, as formulations for the ocular administration of norketotifen have previously not been developed. Ocular formulations of ketotifen have been described (U.S. Pat. No. 6,455,547) but are of no relevance for norketotifen since the physicochemical properties for norketotifen HF are vastly different from those of ketotifen—as an example, the water solubility for ketotifen is about 12.5 mg/ml and the water solubility of norketotifen is about 2.16 mg/ml.
Although hundreds of ophthalmic excipients exist, it is far from obvious what excipients may be compatible with norketotifen and what combinations of excipients and what concentrations thereof should be used to obtain optimal ophthalmic compositions that may optimize that ocular therapeutic activities and decrease the ocular side effects of norketotifen. This may be due to the fact that norketotifen has physicochemical, chemical and pharmacological properties and side effects that are unique to this specific molecule and therefore, new compositions have to be developed for norketotifen. It is a well-known fact that for example all the different ocular steroids need different ophthalmic formulations (compositions). Each composition is depending on the physicochemical and the pharmacological properties of the active molecule(s) and the therapeutic effects sought. In the case of norketotifen, our research has now arrived at compositions that are acceptable to the patients, therapeutically efficacious, allowing for once-daily ocular administration or for repeated daily ocular administrations to mammals in need thereof, while decreasing or even inhibiting certain ocular side effects of norketotifen. Selected ocular compositions have now been found, which offer pharmaceutical compatibility between the active ingredient and the excipients, optimize the therapeutic activities of norketotifen and decrease the ocular side effects thereof.
The preferred formulations of the present invention, as described herein are chemically stable and commercially feasible to manufacture.
It is an objective of the present invention to provide ocular compositions that deliver therapeutically effective concentrations of norketotifen to the eye and the conjunctival tissues, which allow for once-daily ocular administration or for repeated ocular administrations from two to five times daily to a mammal in need thereof, while not causing ocular side effects, such as burning, redness or irritation, and while at the same time being stable upon storage. The terms “therapeutically effective (dose)” and “therapeutically efficacious (dose)” refer to a dose that yields therapeutic benefit to patients, which in the present case refers to therapeutic benefit to patients suffering from allergic and/or inflammatory condition(s).
The present invention may be useful for patients in need of medication for ocular inflammatory and ocular allergic disorders and for patients suffering from xerophthalmic disorders. The term “patients” in this document refers to mammals, such as for example humans, dogs and cats. Preferred are human patients.
Patients suffering from ocular allergic and/or inflammatory disorders include individuals being diagnosed as suffering, for example, from various types of conjunctivitis, as for example allergic conjunctivitis, seasonal allergic conjunctivitis, chronic allergic conjunctivitis, atopic keratoconjunctivitis or vernal conjunctivitis. As used herein, the term “conjunctivitis” refers to all forms of the disease. These patients often have symptoms, such as for example hyperemia of the bulbar conjunctiva, discharge, limbal erythema/swelling or erythema/swelling of the eyelids, itching, decreased lacrimation, photophobia, discomfort, foreign body sensation and/or xerophthalmia.
Keratitis is a condition in which the eye's cornea becomes inflamed. Various forms of keratitis exist, such as for example superficial keratitis and deep keratitis. As used herein, the term “keratitis” refers to all forms of the disease.
The terms “dry eye disease” and “xerophthalmia” are used synonymously herein and refer to various disorders that are well known to those skilled in the art of ophthalmology. Examples of xerophthalmic disorders are keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, Sjoegren's syndrome, ocular cicatrical pemphigoid, blepharitis, corneal injury, infections, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamin A deficiency), autoimmune and other immunodeficient disorder and side effects of medications such as for example anticholinergic drugs used for overactive bladder syndrome and urinary urge incontinence. As used herein, the term “dry eye disease” or “xerophthalmia” refer to all forms of the disease.
All compositions intended for use in the eye are required to be sterile, endotoxin-free and foreign particulate free. The term “foreign particulate free” indicates the absence of any particulate matter, but excludes drug particles, controlled release microparticulates and the like. Conventional methods for the manufacture of sterile compositions include sterilization by moist heat (autoclaving), sterilization by dry heat, ethylene oxide sterilization (gaseous sterilization), exposure to ultraviolet rays or to gamma irradiation or sterilization by aseptic processing or filtration through sterilizing grade filters.
Norketotifen formulations for ocular administration that are described herein can be readily processed by standard manufacturing processes, which are well known to those skilled in the art.